Compounds attachable to skin

Abstract

The present application provides compounds which are attachable to skin, in particular hydrogenated genipin compounds and de-glycosylated oleuropein compounds, which are useful, for example, as colorants and sunscreens.

1 - 46 . (canceled) 
     
     
         47 . A topical composition comprising a compound of formula (I), 
       
         
           
           
               
               
           
         
         or a tautomer and/or a pharmaceutically acceptable salt thereof, 
         wherein A 1 , A 2  and A 3  independently from each other represent, 
         a) a color-imparting moiety, 
         b) a UVA and/or UVB absorbing moiety, or 
         c) a C 1 -C 30  moiety, H, hydroxyl, amino, or a halogen; 
         wherein R 1  represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin, 
         wherein L 1 , L 2  and L 3  independently from each other represent a linker group or are absent, and 
         wherein L 1 -A 1  and L 2 -A 2  do not represent a moiety comprising an unsaturated C—C or C—N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; 
         and an excipient suitable for topical administration. 
       
     
     
         48 . The topical composition according to  claim 47 , wherein at least one of A 1 , A 2  and A 3  is a moiety from above group a) or b). 
     
     
         49 . The topical composition according to  claim 47 , wherein one or more of A 1 , A 2  and A 3  represent a color-imparting moiety, wherein said moiety is:
 a) an optionally substituted (hetero)aromatic moiety comprising, in combination with its optional substituents, 4 to 40 carbon atoms, or   b) an optionally substituted conjugated moiety comprising, in combination with its optional substituents, 6 to 40 carbon atoms and at least 3 conjugated C—C double bonds.   
     
     
         50 . The topical composition according to  claim 47 , wherein one or more of A 1 , A 2  and A 3  represents a UVA and/or UVB absorbing moiety, wherein said moiety is:
 a) an optionally substituted (hetero)aromatic moiety comprising, in combination with its optional substituents, 4 to 36 carbon atoms, or   b) an optionally substituted conjugated moiety comprising, in combination with its optional substituents, 4 to 36 carbon atoms, and at least 2 conjugated C—C double bonds.   
     
     
         51 . The topical composition according to  claim 47 , wherein one or more of A 1 , A 2  and A 3  comprises a chromophore (dye moiety) selected from an azo group; a diazo group; a diphenylamine group; a nitroarylamine group; an azine group; an oxazine group; an acridine group; an indoline group; a sulfur dye group, a quinoid or quinone group; an anthraquinoid or anthraquinone group; a xanthene group; a naphthostyryl group; a diaryl methyl or triarylmethyl group; a benzodifuranone-based group; a formazan group; a phthalocyanine group; or a metal complex, and/or
 wherein one or more of A 1 , A 2  and A 3  comprises a UVA and/or UVB absorbing moiety and being selected/derived from benzophenone group, a benzotriazole group, a benzone group, salicylic acid or a salicylic acid derivative, a benzocaine group, an esculin or an esculin derivative, a ferulic acid or a ferulic acid derivative, octinoxate or an octinoxate derivative, or octocrylene or an octocrylene derivative.   
     
     
         52 . The topical composition according to  claim 47 , wherein L 1  and L 2  are present and independently from each other represent optionally substituted hydrocarbon moieties each comprising, in combination with their optional substituents, 1 to 8 carbon atoms; or wherein L 1  and L 2  form a 5-, 6-, 7- or 8-membered ring. 
     
     
         53 . The topical composition according to  claim 47 , wherein the C 1 -C 30  moiety comprises 1 to 30 carbon atoms; 0 to 12 oxygen atoms; 0 to 8 nitrogen atoms; 0 to 6 sulfur atoms; and 0 to 10 halogen atoms, and/or
 wherein the C 1 -C 30  moiety is selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 30 carbon atoms; 0 to 12 oxygen atoms; 0 to 8 nitrogen atoms; 0 to 6 sulfur atoms; and 0 to 10 halogen atoms; and/or wherein the C 1 -C 30  moiety is bound to L 1 , L 2  and L 3 , respectively, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom.   
     
     
         54 . The topical composition according to  claim 47 , wherein L 1  and L 2  are present and independently from each other represent optionally substituted hydrocarbon moieties each comprising, in combination with their optional substituents, 1 to 8 carbon atoms; or wherein L 1  and L 2  form a 5-, 6-, 7- or 8-membered ring, and/or
 wherein L 1  and OR 1 , together with the carbon atoms to which they are attached, form a 5- or 6-membered lactone, and/or   wherein R 1  represents hydrogen or a C 1-6  acyl.   
     
     
         55 . The topical composition according to  claim 47 , wherein the compound of formula (I) is a compound of formula (II), 
       
         
           
           
               
               
           
         
         or a tautomer and/or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  and R 3  independently from each other represent H; a C 1 -C 30  moiety comprising 1 to 30 carbon atoms; 0 to 12 oxygen atoms; 0 to 8 nitrogen atoms; 0 to 6 sulfur atoms; and 0 to 10 halogen atoms; —SO 3 H; —NO 2 ; —NH 2 ; —OH; —SH; or halogen, and, in case of R 3 , oxo; 
         R 2  is selected from H or a protective group hydrolysable under physiological conditions after application in a topical composition onto skin; and 
         optionally wherein (L) n R 3  and OR 2 , together with the carbon atoms to which they are attached, form a tetrahydrofuran ring which is optionally substituted with OR a1  or oxo; 
         n is 0 or is an integer selected from 1 to 10, wherein, if n=0, (L) n  represents a bond; 
         each L is independently selected from C(═O), N(R N ), O, (—C 1-3  alkylene-O—) x , (—O—C 1-3  alkylene-) x , and —C 1-3  alkylene-, wherein each x is independently an integer from 1 to 10 and each C 1-3  alkylene is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, halo, amino, and carboxy; 
         each R N  is independently selected from H and C 1-3  alkyl. 
       
     
     
         56 . The compound or composition according to  claim 55 , wherein R 1  and/or R 3  represent said C 1 -C 30  moiety which further is a color-imparting moiety, or wherein R 1  and/or R 3  represent said C 1 -C 30  moiety which further is a UVA and/or UVB absorbing moiety. 
     
     
         57 . The composition according to  claim 55 , wherein the compound of formula (II) is a compound of formula (III), 
       
         
           
           
               
               
           
         
       
     
     
         58 . The composition according to  claim 55 , wherein the C 1 -C 30  moiety of R 3  is attached to (L) n  or the cyclopentyl ring of formula (II) via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, and/or
 wherein the C 1 -C 30  moiety of R 1  is attached to (L) n  or to the 3,4-dihydro-2H-pyran ring of formula (II) via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom.   
     
     
         59 . The composition according to  claim 55 , wherein (L) n R 3  represents R a , O—R a , SR a , (CH 2 ) 1-4 —O—R a , C(O)R a , CO 2 R a , O—C(O)R a , NR a   2 , NHR a , NHC(O)R a , NR a C(O)R a , or oxo, wherein R a  independently from each other represents a C 1 -C 18  moiety comprising 1 to 30 carbon atoms; 0 to 12 oxygen atoms; 0 to 8 nitrogen atoms; 0 to 6 sulfur atoms; and 0 to 10 halogen atoms. 
     
     
         60 . The composition according to  claim 56 , wherein (L) n R 1  represents CO 2 R a , C(O)R a  or R a , wherein R a  represents optionally substituted phenyl. 
     
     
         61 . The topical composition according to  claim 47 , wherein the compound of formula (I) is a compound of formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from H and C 1-6  alkyl; 
         R 2  is selected from H and an acyl; 
         n is 0 or an integer selected from 1 to 10, wherein, if n=0, (L) n  represents a bond; 
         each L is independently selected from C(═O), N(R N ), (—C 1-3  alkylene-O—) x , (—O—C 1-3  alkylene-) x , and —C 1-3  alkylene-, wherein each x is independently an integer from 1 to 10 and each C 1-3  alkylene is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, halo, amino, and carboxy; 
         each R N  is independently selected from H and C 1-3  alkyl; and 
         R 3  is a dye moiety, 
         or 
         wherein the compound of formula (I) is a compound of formula (VIII): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is a dye moiety; 
         R 2  is selected from H and an acyl; and 
         R 3  is selected from C 1-6  alkyl, C 2-6  alkenylene, C 2-6  alkynylene, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a2  and oxo, wherein each of said C 1-6  alkyl, C 2-6  alkenylene, and C 2-6  alkynylene is optionally substituted with 1 or 2 substituents independently selected from OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , and C(O)OR a2 ; 
         or wherein R 3  and OR 2 , together with the carbon atoms to which they are attached form a tetrahydrofuran ring, which is optionally substituted with OR a1  or oxo; 
         each R a1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a hydroxyl-protecting group; 
         each R a2  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a carboxyl-protecting group; 
         each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and an amino-protecting group; and 
         each R b1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl. 
       
     
     
         62 . The topical composition according to  claim 47 , wherein the compound of formula (I) is a compound of formula (IX): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from H and C 1-6  alkyl; 
         R 2  is selected from H and an acyl; 
         n is 0 or an integer selected from 1 to 10, wherein, if n=0, (L) n  represents a bond; 
         each L is independently selected from C(═O), N(R N ), O, (—C 1-3  alkylene-O—) x , (—O—C 1-3  alkylene-) x , and —C 1-3  alkylene-, wherein each x is independently an integer from 1 to 10 and each C 1-3  alkylene is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, halo, amino, and carboxy; 
         each R N  is independently selected from H and C 1-3  alkyl; and 
         R 3  is a UV-absorbing moiety, 
         or 
         wherein the compound of formula (I) is a compound of formula (X): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is a UV-absorbing moiety; 
         R 2  is selected from H and an acyl; and 
         R 3  is selected from C 1-6  alkyl, C 2-6  alkenylene, C 2-6  alkynylene, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a2  and oxo, wherein each of said C 1-6  alkyl, C 2-6  alkenylene, and C 2-6  alkynylene is optionally substituted with 1 or 2 substituents independently selected from OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , and C(O)OR a2 ; 
         or wherein R 3  and OR 2 , together with the carbon atoms to which they are attached form a tetrahydrofuran ring, which is optionally substituted with OR a1  or oxo; 
         each R a1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a hydroxyl-protecting group; 
         each R a2  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a carboxyl-protecting group; 
         each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and an amino-protecting group; and 
         each R b1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl. 
       
     
     
         63 . The topical composition according to  claim 47  wherein the compound of formula (I) is a compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from H and a carboxylic acid-protecting group; 
         R 2  is as defined in claim  9 ; and 
         R 3  is selected from C 1-6  alkyl, C 2-6  alkenylene, C 2-6  alkynylene, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a2  and oxo, wherein each of said C 1-6  alkyl, C 2-6  alkenylene, and C 2-6  alkynylene is optionally substituted with 1 or 2 substituents independently selected from OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , and C(O)OR a2 ; 
         or wherein R 3  and OR 2 , together with the carbon atoms to which they are attached form a tetrahydrofuran ring, which is optionally substituted with OR a1  or oxo; 
         each R a1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a hydroxyl-protecting group; 
         each R a2  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a carboxyl-protecting group; 
         each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and an amino-protecting group; and 
         each R b1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl. 
       
     
     
         64 . A non-therapeutic method of semi-permanently tattooing skin of a subject or a non-therapeutic method of protecting skin of a subject from UV sunlight, the method comprising applying to the skin of the subject the topical composition of  claim 47 . 
     
     
         65 . A compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from H and a carboxylic acid-protecting group; 
         R 2  is selected from H or a protective group hydrolysable under physiological conditions after application in a topical composition onto skin; and 
         R 3  is selected from C 1-6  alkyl, C 2-6  alkenylene, C 2-6  alkynylene, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a2  and oxo, wherein each of said C 1-6  alkyl, C 2-6  alkenylene, and C 2-6  alkynylene is optionally substituted with 1 or 2 substituents independently selected from OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , and C(O)OR a2 ; 
         or wherein R 3  and OR 2 , together with the carbon atoms to which they are attached form a tetrahydrofuran ring, which is optionally substituted with OR a1  or oxo; 
         each R a1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a hydroxyl-protecting group; 
         each R a2  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and a carboxyl-protecting group; 
         each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and an amino-protecting group; and 
         each R b1  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl. 
       
     
     
         66 . A compound according to  claim 65 , wherein the compound of formula (IV) is selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof: 
       
         
           
                 
               
                     
                 
                   Structure